Background: Sulfotransferase family comprises key enzymes involved in drug metabolism. Oxamniquine
is a pro-drug converted into its active form by schistosomal sulfotransferase. The conformational
dynamics of side-chain amino acid residues at the binding site of schistosomal sulfotransferase towards
activation of oxamniquine has not received attention.
Objective: The study investigated the conformational dynamics of binding site residues in free and oxamniquine
bound schistosomal sulfotransferase systems and their contribution to the mechanism of oxamniquine
activation by schistosomal sulfotransferase using molecular dynamics simulations and binding
Methods: Schistosomal sulfotransferase was obtained from Protein Data Bank and both the free and oxamniquine
bound forms were subjected to molecular dynamics simulations using GROMACS-4.5.5 after
modeling it’s missing amino acid residues with SWISS-MODEL. Amino acid residues at its binding site
for oxamniquine was determined and used for Principal Component Analysis and calculations of side-chain
dihedrals. In addition, binding energy of the oxamniquine bound system was calculated using g_MMPBSA.
Results: The results showed that binding site amino acid residues in free and oxamniquine bound sulfotransferase
sampled different conformational space involving several rotameric states. Importantly,
Phe45, Ile145 and Leu241 generated newly induced conformations, whereas Phe41 exhibited shift in equilibrium
of its conformational distribution. In addition, the result showed binding energy of -130.091 ±
8.800 KJ/mol and Phe45 contributed -9.8576 KJ/mol.
Conclusion: The results showed that schistosomal sulfotransferase binds oxamniquine by relying on hybrid
mechanism of induced fit and conformational selection models. The findings offer new insight into sulfotransferase
engineering and design of new drugs that target sulfotransferase.